Two major findings in the previous funding period will be pursued in the proposed 5-year extension period. First, we showed that a single experience with operant self-administration of ethanol produces a robust dopamine response on the second day of ethanol consumption, but not the first, and this accompanies an increase in ethanol consumption. Aim 1 will test the hypothesis that it is the central effects of ethanol that the rats experience that leads to the behavioral and neurochemical changes. This will be done by limiting a group of rats so that they self-administer a dose of ethanol <0.25 g/kg. In addition, we propose to further characterize the time course of persistence of the behavioral and neurochemical response to a single exposure to operant ethanol self-administration. We predict that both the consumption and accumbal dopamine response will decay in a parallel manner which would be consistent with our interpretation that the dopamine response is part of a reward prediction system in the brain. A final part of this aim will be to do tract tracing to try to discover an anatomical basis for the subregional specificity of the dopamine response during consumption. Aim 2 will focus on the prefrontal cortex and orbitofrontal cortex. Previous work indicated that the dopamine increases in the prefrontal cortex in rats that had been trained for one week to operantly self-administer sucrose or sucrose/ethanol solutions. We now propose to examine whether these responses In the prefrontal cortex develop after a single exposure to ethanol or sucrose. Furthermore we propose to extend the studies to measure norepinephrine in cortical dialysates, another important monoamine in the cortex. Also, we plan to study the orbitofrontal cortex, an area involved in decision making that has recently been found to be affected by ethanol. Aim 3 will be a new direction, i.e., examination of the role of a neuroimmune factor, MCP-1, in ethanol self-administration. Both the agonist and antagonist will be infused into the ventricles and the acquisition of operant self-administration will be measured as well as the escalation of drinking after induction of physical dependence using a vapor chamber model.